Pharmacokinetic interaction between voriconazole and methadone at steady-state in patients on methadone therapy
Author:
Liu P, Foster G, Labadie R, Somoza E, Sharma A
Date: 22 November 2006
Abstract:
This trial was aimed to estimate the pharmacokinetic interaction between voriconazole and methadone at steady-state in male patients on methadone therapy and to characterize the safety and tolerability profile during the co-administration. Twenty-three patients on individualized methadone therapy (30 – 100 mg once daily) were enrolled into this randomized, patient- and investigator-blind, placebo-controlled, parallel group study. Methadone pharmacokinetic samples were collected from patients receiving methadone alone as the baseline before they were randomized to co-administer either 200 mg twice daily (BID) voriconazole (400 mg BID loading doses on the first day) (n = 16) or matching placebo (n = 7) for the next 5 days. Pharmacokinetic samples for methadone and voriconazole were collected on the last day of voriconazole dosing. The safety data were collected throughout the study. Voriconazole increased the steady-state exposure of pharmacologically active enantiomer (R)-methadone: the mean area under the concentration-time curve (AUC0-24) by 47.2% (90% CI: 37.7%, 57.4%) and the mean peak concentration (Cmax) by 30.7% (90% CI: 22.2%, 39.8%). The magnitude of increase in (S)-methadone exposure was greater than that of (R)-methadone: AUC0-24: 103.4% (90% CI: 85.0%, 123.6%); Cmax: 65.4% (90% CI: 52.6%, 79.2%). Methadone appeared to have no effect on the steady-state voriconazole pharmacokinetics compared to the historical data of voriconazole alone. Methadone patients receiving voriconazole showed no signs or symptoms of significant opioid withdrawal or overdose. Co-administration of 200 mg BID voriconazole with methadone was generally safe and well-tolerated. Nevertheless, caution should be exercised when voriconazole is co-administered with methadone due to the increase in (R)-methadone exposure, which in turn may require dose reduction of methadone.
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